Zentrum für Humangenetik Bremen
Universität Bremen, Leobener Str. ZHG, D-28359 Bremen
Breast tumors are the most common tumors at all. During their lifetime about 8-10% of all women come down with a malignant breast tumor. Especially affected are women between age 45-50 and 60-65. Factors contributing to the development may be ionizing radiation, a diet high in saturated fat, and long-term intake of estrogens. Only about 5-10% of all breast tumors have a family origin that is associated with a detectable alteration of a specific gene. More information on different tumor forms etc. may be found here (information for patients and professionals).
During the past 10-15 years numerous cytogenetic and molecular genetic investigations were conducted to obtain new diagnostic/prognostic factors to, on the long run, develop new therapies.
Cytogenetic investigations e.g. showed that trisomy 8 is an early clonal aberration in a subtype of ductal carcinoma (Bullerdiek et al., Cancer Genet. Cytogenet. 1993, 65(1):64-7). According to a recent study this is associated with a worse prognosis, independent of age, lymph node metastasation or tumor size (Tagawa et al., Med. Oncol. 2003, 20(2):127-36).
At a molecular genetic level it was found that aberrations of the genes BRCA1 (located on chromosome 17) and BRCA2 (located on chromosome 13) contribute to an elevated risk for breast tumors. This especially applies to breast tumors with a family history. In non-familial tumors a specific deletion in the CHEK2 gene (located on chromosome 22) was found to contribute to a higher risk (Meijers-Heijbojer et al., Nat. Genet. 2002, 31(1):55-9). All three gene products play a part in transcription and repair and through the gene aberrations their functions are changed.
Lately a particular important success was achieved in treating metastasised tumors showing a HER-2 overexpression which up to now was associated with a very poor prognosis. In the meantime a new drug on antibody basis was developed that leads to an improved prognosis. Further derivates are in the developmental phase.
For some years research on the influence of genes of the High Mobility Group on origin and/or progression of breast tumors has been under way to develop further agents for diagnosis, prognosis, and possibly treatment. It was found that expression of HMGI-C in a subgroup of tumors, invasive ductal carcinoma, correlates with histological grading. In the lobular tumors analysed no expression was found (Rogalla et al., Mol. Carcinogen. 1997, 19:153-156). In a newer investigation a correlation between tumor grading and HMGA1 expression was confirmed (Flohr et al., Histol. Histopathol. 2003, 18:999-1004) and therefore the potential usefulness as a further prognostic factor.
The exact mechanism of action of HMGA1 in breast cancer is still unknown but it was demonstrated that HMGA1 protein binds to the BRCA1 promoter and inhibits it. In aggressive sporadic tumors with a drastically reduced BRCA1 expression an inverse correlation between HMGA1 and BRCA1 protein expression was found which hints on an influence of HMGA1 on transcriptional regulation of BRCA1 (Baldassare et al., Mol. Cell Biol. 2003, 23:2225-2238).